Melanoma switches phenotypes to become metastatic and drug-resistant

Phenotype switching may be involved in changing the appearance of melanoma tumors by altering the number and type of protein receptors that dot the surface of the individual melanoma cells within a tumor. Identifying the phenotype that patients exhibit may help determine which patients are more likely to benefit from existing medications while also providing an opportunity to create new targeted therapies.

“We were able to demonstrate for the first time that different receptors within a single signaling pathway—in this case, the Wnt signaling pathway—can guide the phenotypic plasticity of tumor cells, and increased signaling of Wnt5A in particular can result in an increase in highly invasive tumor cells that are less sensitive to existing treatments for metastatic melanoma,” said Ashani Weeraratna, PhD, of The Wistar Institute in Philadelphia, Pennsylvania.

While melanoma accounts for less than 5% of all cases of skin cancer, it is the deadliest form of the disease, resulting in the majority of deaths related to skin cancer, according to the American Cancer Society. The 5-year survival rate for patients with metastatic melanoma is about 15% to 20%, and although new, targeted therapies designed to combat the disease based on a person's genetics have become available in recent years, some of these drugs are not effective in many patients, and many who do respond well to the drugs often eventually become resistant to them.

Weeraratna's team focused on Wnt5A, a Wnt signaling molecule that has been found in increased levels in metastatic melanomas. In order for Wnt5A to promote the phenotype switch from early in the tumor's formation to the time it becomes metastatic, the tyrosine kinase receptor ROR2 is required. When ROR2 is not present, Wnt5A is unable to promote tumor metastasis. The only other member of the family that has been identified is ROR1, and this research was done to determine what role ROR1 might play in the progression of melanoma.

The researchers were able to determine that ROR1 inhibited the invasion of melanoma cells, and ROR1 was targeted for degradation by Wnt5A and ROR2. When ROR1 was silenced, the researchers observed that there was an increased rate of invasion of melanoma cells both in vitro and in vivo.

In addition to laboratory studies in cells and mice, the researchers tested their hypotheses in a small cohort of patients. They found that seven out of nine patients who demonstrated less than a 33% clinical response to vemurafenib had a positive expression of Wnt5A, and only two of the remaining 15 patients who had a 38% or greater clinical response to vemurafenib exhibited any Wnt5A expression.

Additionally, in eight patients who had undergone BRAF inhibitor therapy, the levels of Wnt5A were much lower in tumor cells prior to therapy compared to cells that were tested for Wnt5A after those same patients had relapsed. The study was published in Cancer Discovery (2013; doi:10.1158/2159-8290.CD-13-0005).